Navigating the genodermatoses maze

"There are more than 220 genetic skin disorders. Each one takes a lot of time to unravel," Moise L. Levy, M.D., says.

Dr. Levy, who is a professor of dermatology and pediatrics at Baylor College of Medicine and chief of the dermatology service at Texas Children's Hospital (both in Houston), notes that the practitioners most likely to remain in the genetic trenches are those interested in basic sciences and those working with children, since inherited diseases are, by definition, a large part of their practices.

Online resources

Dr. Levy tells Dermatology Times, "Most practitioners will go through a similar decision making process.

"If, for example, a dermatologist sees a child with dry skin and missing teeth, she or he is likely to think, 'This is different but vaguely familiar.'"

Suspecting a genetic disorder, some dermatologists will immediately make a referral to a specialist. Others try to diagnose first. Commercial Web sites, such as the London Dysmorphology database, offer fee-based information. However, the Online Mendelian Inheritance of Man (OMIM) database is usually the best place to start. This catalogue of inherited diseases is frequently updated, free of charge and reputable, funded by the National Institutes of Health (NIH).

Using the Web site's search engine, a dermatologist can type in "missing teeth" and "dry skin." This produces two hits - ectodermal dysplasia and oculotrichodysplasia. If the physical exam turned up neurological involvement, then a physician may suspect the former.

In that case, two additional Web sites are helpful. http://GeneTests.org/ (also operated by the NIH) lists clinical and research test sites by disease. That simplifies the referral process. Alternatively, dermatologists in remote areas, or those with patients unwilling or unable to travel, can turn to http://Genedx.com/ for mail order genetic testing.

Sometimes diagnosing a condition isn't difficult. For example, most dermatologists will recognize the diffuse blistering of epidermolysis bullosa (EB). But knowing which genes are involved - and where the mutation took place - may illuminate disease progression and prognosis. Fortunately, EB is one of a small but growing number of skin diseases where molecular diagnosis is possible.

State of the genetic art

Not that long ago, scientists thought one mutated gene caused one specific disease. Reality has proven to be more complicated.

First, it can take any number of mutations to produce a particular disease entity. Several genetic events are required, for example, to overcome senescence and induce melanoma.

Second, the location (or size) of a mutation can influence its clinical presentation. For example, one patient with an incontinentia pigmenti (IP)/NEMO gene mutation might present with classical IP, showing staged skin eruptions with or without dental, neurological and eye problems. Another patient will develop ecotodermal dysplasia - absent or malformed teeth, sweating abnormalities and severe immunodeficiency.

Third, any given gene mutation may be a pathway to multiple diseases. For example, RECQL4 mutations cause both Rothmund-Thomson syndrome (RTS) and RAPADILINO (which involves short stature and radial anomalies but not the cancer risk associated with RTS patients).

"Scientists are beginning to think in terms of gene function," Dr. Levy says, "not dysfunction. And we're not that far from understanding the mechanism of action for many dermatological diseases, which is ultimately the key to treating them."